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Spirometry conducted to internationally accepted standards. Trough FEV1 defined as the mean of the FEV1 measurements at 23 h 10 min and 23 h 45 min post the Day 84 morning dose. The primary variable (imputed with last observation carried forward) will be analysed using a mixed model for the Per Protocol Set (PPS). The model will contain treatment as a fixed effect with the baseline FEV1 measurement, FEV1 prior to inhalation and FEV1 10-15 min post inhalation of salbutamol (components of reversibility at Visit 1) as covariates.

Spirometry conducted to internationally accepted standards. Trough FEV1 defined as the mean of the FEV1 measurements at 23 h 10 min and 23 h 45 min post the Day 84 morning dose. The primary variable (imputed with last observation carried forward) will be analysed using a mixed model for the Per Protocol Set (PPS). The model will contain treatment as a fixed effect with the baseline FEV1 measurement, FEV1 prior to inhalation and FEV1 10-15 min post inhalation of salbutamol (components of reversibility at Visit 1) as covariates.

The standardized (with respect to the length of time) AUC for FEV1 will be calculated between 5 min and 4 h post morning dose as the sum of trapezoids divided by the length of time at Day 84 (Visit 6) and Day 182 (Visit 10). Scheduled (not actual) time points are to be used. FEV1 measurements taken within 6 h of rescue use will be set to missing before the standardized AUC is calculated.

The Transition Dyspnea Index (TDI) total score after 12 and 26 weeks of treatment will be analyzed using the same mixed model as specified for the primary analysis with the Baseline Dyspnea Index (BDI) total score as the baseline.Total score ranging - 9 to + 9. The lower the score, the more deterioration in severity of dyspnea. One additional option in each category, which does not contribute to the score, allows for circumstances in which impairment is due to reasons other than dyspnea.

The number of exacerbations during the 26 week treatment period will be analyzed using a generalized linear model assuming a negative binomial distribution.

Mean Daily Number of Puffs of Rescue Medication Used Over 26 Weeks of Treatment [ Time Frame: 12 and 26 weeks ]

The mean daily number of puffs of rescue medication taken by the patient will be derived. If the number of puffs is missing for part of the day (either morning or evening) then a half day will be used in the denominator. Rescue medication data recorded during the 14 day run-in period will be used to calculate the baseline. The mean change from baseline in the daily number of puffs of rescue medication will be analyzed using the same mixed model as specified for the primary analysis, with the baseline FEV1 replaced with the baseline daily rescue use.

Rescue Medication Use Over 26 Weeks: Percentage of 'Days With no Rescue Use' [ Time Frame: 26 weeks ]

A 'day with no rescue use' is defined from diary data as any day where the patient has taken no puffs of rescue medication. The percentage of 'days with no rescue use' will be derived and analyzed as for the percentage of 'nights with no nighttime awakenings'.

A Total and three component scores are calculated: Symptoms; Activity; Impacts. Each component of the questionnaire is scored separately:The score for each component is calculated separately by dividing the summed weights by the maximum possible weight for that component and expressing the result as a percentage: Score = 100 x Summed weights from all positive items in that component divided by Sum of weights for all items in that component The Total score is calculated in similar way: Score = 100 x Summed weights from all positive items in the questionnaire divided by Sum of weights for all items in the questionnaire Sum of maximum possible weights for each component and Total: Symptoms 566.2 Activity 982.9 Impacts 1652.8 Total (sum of maximum for all three components) 3201.9 The proportion of patients who achieve a clinically important improvement of at least 4 units in the total SGRQ will be analyzed. The higher the score the more symptoms of disease are present.

Original Secondary Outcome Measures ICMJE (submitted: March 14, 2012)

Trough FEV1 [ Time Frame: 26 weeks ]

Trough FEV1 is defined as the average of the 23 h 10 min and the 23 h 45 min values taken in the clinic at Visit 11. At Visits 4, 5, 6 and 10 trough FEV1 is defined as the average of the 50 min and the 15 min pre-dose values taken in the clinic.

FEV1 [ Time Frame: 26 weeks ]

FEV1 at each time point, for each visit, will be analyzed using the same mixed model as specified for the primary analysis. Least squares means will be displayed by treatment group along with the estimated treatment differences and the associated 95% confidence intervals and 2-sided p-values.

FVC [ Time Frame: 26 weeks ]

FVC at each time point, for each visit, will be analyzed using the same mixed model as specified for the primary analysis. Least squares means will be displayed by treatment group along with the estimated treatment differences and the associated 95% confidence intervals and 2-sided p-values.The standardized (with respect to the length of time) AUC for FEV1 will be calculated between 5 min and 4 h post morning dose as the sum of trapezoids divided by the length of time at Day 84 (Visit 6) and Day 182 (Visit 10).

Standardized AUC (5min-4h) for FEV1 [ Time Frame: 12 and 26 weeks ]

The standardized (with respect to the length of time) AUC for FEV1 will be calculated between 5 min and 4 h post morning dose as the sum of trapezoids divided by the length of time at Day 84 (Visit 6) and Day 182 (Visit 10). Scheduled (not actual) time points are to be used. FEV1 measurements taken within 6 h of rescue use will be set to missing before the standardized AUC is calculated.

Transition Dyspnea Index [ Time Frame: 12 and 26 weeks ]

The Transition Dyspnea Index (TDI) total score after 12 and 26 weeks of treatment will be analyzed using the same mixed model as specified for the primary analysis with the Baseline Dyspnea Index (BDI) total score as the baseline.

COPD Exacerbations [ Time Frame: 26 weeks ]

The number of exacerbations during the 26 week treatment period will be analyzed using a generalized linear model assuming a negative binomial distribution.

Mean daily rescue medication use [ Time Frame: 26 weeks ]

The mean daily number of puffs of rescue medication taken by the patient will be derived. If the number of puffs is missing for part of the day (either morning or evening) then a half day will be used in the denominator. Rescue medication data recorded during the 14 day run-in period will be used to calculate the baseline. The mean change from baseline in the daily number of puffs of rescue medication will be analyzed using the same mixed model as specified for the primary analysis, with the baseline FEV1 replaced with the baseline daily rescue use.

Percentage of days with no rescue medication use [ Time Frame: 26 weeks ]

A 'day with no rescue use' is defined from diary data as any day where the patient has taken no puffs of rescue medication. The percentage of 'days with no rescue use' will be derived and analyzed as for the percentage of 'nights with no nighttime awakenings'.

The total score of SGRQ-C and handling of missing data will be conducted in accordance with the user guide.

The SGRQ total score at Weeks 12 and 26 will be summarized by treatment and analyzed using a mixed model for the FAS. The same model as specified for the primary analysis was used, however, with baseline SGRQ total score instead of baseline FEV1 as covariate.

Adverse event data [ Time Frame: 26 weeks ]

All study emergent adverse events will be summarized and listed. Adverse events starting on or after the time of the first treatment of study drug but not later than 7 days (30 days in the case of a serious adverse event) after the last treatment will be classified as a treatment emergent adverse event.

ECG [ Time Frame: 26 weeks ]

Data from the electrocardiogram will be summarized by treatment. The maximum post first dosing (i.e. post baseline) value will also be summarized. Changes from baseline will also be summarized by treatment.

Vital signs [ Time Frame: 26 weeks ]

Vital signs data will be summarized by treatment. All data will be included in the analysis regardless of rescue medication usage.

The number (%) of patients with notable values for vital signs and notable changes from baseline will be summarized.

Biochemistry, haematology, urinalysis data [ Time Frame: 26 weeks ]

All laboratory data will be summarized by treatment. Shift tables relative to the normal reference ranges will be used to summarize the change from baseline to post-dose values at each scheduled time point.

The purpose of this study is to compare the effectiveness and safety of indacaterol with salmeterol /fluticasone propionate treatment in patients with moderate chronic obstructive pulmonary disease who, on entry to the study are being treated with salmeterol /fluticasone propionate.